Table 1.
Clinical trials using CTLA-4 and PD/PD-L1 checkpoint inhibitors
| Checkpoint inhibitors | Study number | Phase | Status | Study design | Study population | Primary outcome measures | Secondary outcome measures | No. of patients (estimated enrollment) | Final results |
| Nivolumab, Ipilimumab | NCT03342417 | II | Recruiting | NIVO + IPI | -Neoadjuvant breast cancer -Platinum-resistant advanced ovarian/GC | - % AE | - DOR, OS, QOL, recurrence rate | 60 | Pending |
| Nivolumab, Ipilimumab | NCT02872116 (CHECKMATE-649) | III | Recruiting | - NIVO + IPI/ -NIVO + chemo vs chemotherapy (XELOX/FOLFOX) | -Naive advanced/metastatic GC/GEJ | -OS NIVO + IPI vs chemo (PD-L1 + tumors) -OS NIVO + chemo vs chemo -ORR, PFS nivo + chemo vs chemo | -OS NIVO + IPI vs chemo -PFS NIVO + IPI/ NIVO + chemo vs chemo (PD-L1+) -ORR NIVO + chemo vs chemo | 1349 | Pending |
| Nivolumab, Ipilimumab | NCT02935634 (FRACTION-GC) | II | Recruiting | - NIVO + IPI -NIVO + RELATLIMAB -NIVO + BMS-986205 | -Advanced GC | -ORR, DOR, PFS | -% AE, SAE, discontinuation/death due to treatment | 300 | Pending |
| Nivolumab, Ipilimumab | NCT03044613 | Ib | Recruiting | - NIVO/NIVO + IPI prior to chemoradiation + NIVO | -Neoadjuvant treatment, resectable stage II/III EC/GEJ | -% AE | -Feasibility of induction treatment -Path CR -Quantity of NIVO bound to PD1 receptor -Changes in expression of immune markers -OS, RFS | 32 | Pending |
| Nivolumab, Ipilimumab | NCT03443856 (VESTIGE) | II | Not yet recruiting | - NIVO + IPI | -Adjuvant treatment GC/GEJ adenocarcinoma stage Ib-IVa, ↑risk of recurrence (ypN1-3 + /R1) after neoadjuvant treatment + resection | -DFS | -OS -Relapse rate -Loco-regional/distant failure rates -% AE, QOL, global health status | 240 | N/A |
| Nivolumab, Ipilimumab | NCT03409848 (INTEGA) | II | Recruiting | -IPI/FOLFOX + NIVO and TRAS | -Advanced/metastatic GC adenocarcinoma, previously untreated | -OS | -% AE -PFS, RR, QOL -Translational research -Central imaging review | 97 | Pending |
| Nivolumab, Ipilimumab | NCT02834013 | II | Recruiting | -NIVO + IPI | -Rare tumors, including gastric NET, SqCC, GIST | -ORR-RECIST | -Toxicities -OS, PFS -Clinical benefit rate -ir-ORR/PFS | 707 | Pending |
| Nivolumab, Ipilimumab | NCT03126110 | I/II | Recruiting | -NIVO + INCAGN01876 -IPI + INCAGN01876 -NIVO + IPI + INCAGN01876 | -Advanced/metastatic malignancies, including GC | -Toxicities (%AE) -ORR-RECIST | -DR, DDC, PFS, OS- RECIST | 450 | Pending |
| Nivolumab, Ipilimumab | NCT03241173 | I/II | recruiting | -NIVO + INCAGN0949 -IPI + INCAGN0949 -NIVO + IPI + INCAGN0949 | -Advanced/ metastatic malignancies, including GC | -Toxicities (%AE) -ORR-RECIST | -DR, DDC, PFS, OS- RECIST | 651 | Pending |
| Ipilimumab | NCT01585987 | II | Completed | -IPI vs BSC (5-FU) | -Unresectable/ metastatic GC/GEJ adenocarcinoma (following Ist line treatment) | -ir-PFS (ir RECIST) -% BOR | -PFS (mWHO) -OS | 143 | -ir-PFS ↓ (2.92 vs 4.89 mo); -mWHO-PFS↓ (2.72 vs 4.89) (P = 0.03); -OS at study completion 12.68 vs 12.06 mo |
| Tremelimumab, Durvalumab | NCT02658214 | I | Recruiting | -TREME + DURVA + chemo (platinum-based SOC) | -Ist line locally advanced/ metastatic solid tumor, including GC/GEJ | -Laboratory findings -%AE, safety, tolerability -Tumor assessment (RECIST) | - | 42 | Pending |
| Nivolumab | NCT03453164 (CIRCUIT) | I/II | Recruiting | NIVO + radiotherapy | -Unresectable recurrent GC (3 rd line) | -DCR: -PD: on CT/ MRI/ PET-CT -CR/PR/SD | -Mean survival -% AE -Local control rate -% PL-L1+, MHCI- tumor cells -Cytokines serum concentration -% regT cells -% Ag-specific CTL | 40 | Pending |
| Nivolumab | NCT02267343 | III | Active, not recruiting | NIVO vs placebo | -Refractory, unresectable, advanced/ recurrent GC/GEJ | -OS, PFS | -ORR, DOR, %AE, %SAE, safety | 480 | Pending |
| Nivolumab | NCT02746796 | II/III | Recruiting | NIVO + chemo | -Ist line therapy, unresectable advanced/ recurrent GC/GEJ | -PFS -OS | -ORR, DOR, DCR -TTR, BOR -% AE, SAE, laboratory abnormalities | 680 | Pending |
| Nivolumab | NCT03006705 | III | Recruiting | NIVO + chemo vs placebo + chemo | -Adjuvant treatment p stage III GC/GEJ (after D2 resection) | -RFS | -OS -Safety- % AE, SAE, laboratory abnormalities | 700 | Pending |
| Nivolumab | NCT02999295 | I/II | Recruiting | -NIVO + RAMUCIRUMAB | -Advanced/ recurrent unresectable GC/GEJ | -No. of pts with DLT -6 mo PFS | -%AE -ORR -DCR -OS, PFS | 44 | Pending |
| Nivolumab | NCT02946671 | I | Recruiting | -NIVO + MOGAMULIMUMAB (KW-0761 = anti-CCR4) | -Preoperator treatment against solid cancers, including GC | -% AE - FOXp3 + tumors by immunohistochemistry | -ORR-RECIST -% ↓Treg | 18 | Pending |
| Nivolumab | NCT02951091 (Biomarker – integrated Umbrella) | Observational | Recruiting | -NIVO/ AFATINIB/ GSK2636771 + PACLITAXEL | -Advanced GC -Different molecular cohorts: PD-L1+, MSI-H, EBV+ → NIVO | -PFS | - | 400 | Pending |
| Nivolumab | NCT02465060 (The MATCH screening trial) | II | Recruiting | -NIVO/ other agents (according to genetic testing) | -Advanced/ metastatic solid tumors (including GC), lymphomas, multiple myelomas → mismatch repair deficiency (loss of MLH1/ MLH2) | -ORR | -OS, PFS -TTP | 6452 | Pending |
| Nivolumab | NCT02862535 | Ib | Active, non-recruiting | -ANDECALIXIMAB (GS-5745) ± NIVO/chemo | -Previously treated, advanced GC/GEJ adenocarcinoma (Japan) | -Safety (% AE) | - Serum concentration of Andecaliximab -% Ab-anti Andecaliximab | 36 | N/A |
| Pembrolizumab | NCT03382600 (MK-3475-659/ KEYNOTE 659) | II | Recruiting | -PEMBRO + OXALIPLATIN + TS-1 vs -PEMBRO + CISPLATIN + TS-1 | -Advanced CG/GEJ adenocarcinoma, HER2(-), PD-L1+ | -ORR-RECIST | -ORR (i-RECIST) -DCR, DOR, TTR, PFS (RECIST, iRECIST) -OS, % AE | 90 | Pending |
| Pembrolizumab | NCT02901301 | I/II | Recruiting | -PEMBRO + TRASTUZUMAB + chemo | -Ist line advanced, GC HER2+ | -Recommended dose -ORR-RECIST | -DOR -TTR | 49 | Pending |
| Pembrolizumab | NCT03342937 | II | Recruiting | PEMBRO + XELOX | -Ist line metastatic GC adenocarcinoma | -PFS | -OS - % AE | 50 | Pending |
| Pembrolizumab | NCT02918161 | II | Recruiting | PEMBRO + chemo (SOC) | -Perioperative setting GC/GEJ | -2 years DFS | - Pathol CR -OS, ORR (RECIST) -DFS | 40 | Pending |
| Pembrolizumab | NCT02689284 | I/II | Recruiting | PEMBRO + MARGETUXIMAB | -HER2 + advanced, metastatic GC/GEJ | - Expansion phase dose of Margetuximab -Antitumor activity: RD, ORR (RECIST, ir-RECIST) | -OS -PFS | 72 | Pending |
| Pembrolizumab | NCT03257163 | II | Recruiting | -PEMBRO + CAPECITABINE + radiotherapy (perioperative) | -Mismatch repair deficient, EBV+, operable GC | -RFS | - | 40 | Pending |
| Pembrolizumab | NCT03064490 (PROCEED) | II | Recruiting | -PEMBRO + chemoradiotherapy | -Neoadjuvant treatment, locally advanced EG cancers | -Pathol CR | -Toxicity (% AE) | 38 | Pending |
| Pembrolizumab | NCT02563548 | Ib | Recruiting | -PEMBRO + PEGPH2O (Pegylated Recombinant Human Hyaluronidase) | -Hyaluronan-high (HA-H) patients with relapsed/ refractory cancers (adenocarcinoma) | -ORR | -DCR, DOR, PFS (RECIST, ir-RECIST) | 81 | Pending |
| Pembrolizumab | NCT02954536 | II | Recruiting | -PEMBRO+TRASTUZUMAB+chemo | -Advanced, metastatic HER2+, EG (Ist line) | -PFS (RECIST) | - | 37 | Pending |
| Pembrolizumab | NCT03221426 (MK-3475-585) (KEYNOTE-585) | III | Recruiting | -PEMBRO + cemo vs placebo + chemo | -Neoadjuvant/adjuvant previously untreated GC/GEJ adenocarcinoma | -OS - EFS event-free survival) -Pathol CR -% AE + discontinuation of treatment | -DFS | 860 | Pending |
| Pembrolizumab | NCT03196232 | II | Recruiting | -PEMBRO + EPACADOSTAT | -Metastatic/ unresectable GEJ | -6-mo PFS | -ORR (RECIST) -OS -RR | 30 | Pending |
| Pembrolizumab | NCT03019588 (MK-3475-063/ KEYNOTE-063) | III | Recruiting | -PEMBRO vs chemo (PACLITAXEL) | -Progression after Ist line platinum-fluoropyridine chemo, advanced GC/GEJ adenocarcinoma, PD-L1+ (Asia) | -OS, PFS (RECIST) | -ORR-RECIST -% AE, % discontinuation due to AE | 360 | Pending |
| Pembrolizumab | NCT03488667 | II | Not yet recruiting | PEMBRO + mFOLFOX | -Neoadjuvant treatment GEJ adenocarcinoma -adjuvant treatment GC | -yp RR (pathologic response) -toxicity (% AE) | -ORR, DFS, OS -PET scan response rate - % PD-L1 + in tumor cells | 40 | N/A |
| Pembrolizumab | NCT03413397 | II | Recruiting | PEMBRO + LENVATINIB MESYLATE | -Metastatic/ recurrent GC/GEJ | -ORR-RECIST | -PFS, OS -Characteristic immunologic changes | 29 | Pending |
| Pembrolizumab | NCT02730546 | I/II | Recruiting | PEMBRO + chemoradiotherapy | -Locally advanced, operable, GEJ/gastric cardia adenocarcinoma (neoadjuvant setting) | -Path CR -PFS | -R0 resection, DSF -Dose-limiting AE, % surgical complications, OS, PFS, time to relapse | 68 | Pending |
| Pembrolizumab | NCT02318901 | Ib/II | Active, not recruiting | PEMBRO-TRASTUZUMAB/ADO-TRASTUZUMAB-ETAMSINE/CETUXIMAB | -Unresectable HER2+, advanced GC/GEJ | -Dose of mAb combined with PEMBRO | -% grade 3-4 AE -RR (RECIST, ir-RECIST) -OS, PFS -Circulating tumor DNA -Imaging changes | 90 | N/A |
| Pembrolizumab | NCT03095781 | I | Recruiting | PEMBRO + XL888 (= Hsp90 inhibitor) | -Advanced gastrointestinal cancer (including GC) | -Recommended dose for combined treatment | -ORR, PFS, RS (RECIST) -OS | 50 | Pending |
| Pembrolizumab | NCT02346955 | I | Terminated | -CM-24[MK-6018 = mAb against CEACAM1] ± PEMBRO | -Advanced/recurrent malignancies (including GC) | -% AE, discontinuation due to AE, DLT | -Maximum drug concentration, half-life elimination, ORR, DOR | 27 | Pending |
| Pembrolizumab | NCT02178722 (KEYNOTE-037/ECHO-202) | I/II | Recruiting | -PEMBRO + EPACADOSTAT | -Selected carcinomas (including GC) | -% DTL -ORR | -PFS -% AE -OS | 508 | Pending |
| Pembrolizumab | NCT02903914 | I/II | Recruiting | -PEMBRO + ARGINASE INHIBITOR INCB001158 | - Advanced/metastatic solid tumors (including GC) | -% AE | - Rrecommended dose of arginase Inhibitor ± PEMBRO -Pharmacokinetic profile -Antitumor activity of drugs (RECIST, ir RECIST) | 346 | Pending |
| Pembrolizumab | NCT03122548 | II | Active, not recruiting | PEMBRO + CRS-207 | -Recurrent/metastatic GC/EG (1-2 prior lines of systemic treatment) | -% AE | -Tumor response (RECIST) -OS -Characterization of immune response -Analysis of biomarker expression | 79 | N/A |
| Pembrolizumab | NCT02393248 | I/II | Recruiting | -INCB054828 + PEMBRO/ chemo/ TRASTUZUMAB | -Advanced malignancies (including GC), progression after prior treatment | -Maximum tolerated dose, pharmacodynamic of INCB054828 | -ORR -Maximum/minimum plasma Concentration of NCB054828 | 280 | Pending |
| Pembrolizumab | NCT02494583 | III | Active, not recruiting | -PEMBRO vs -PEMBRO + chemo vs -Placebo + chemo | -Ist line treatment, advanced GC/GEJ | -PFS (RECIST) -OS | -ORR, DOR (RECIST) -QOL | 764 | N/A |
| Pembrolizumab | NCT02370498 (KEYNOTE-061) | III | Active, not recruiting | -PEMBRO vs chemo (PACLITAXEL) | -Advanced GC/GEJ adenocarcinoma, Progressed after Ist line (platinum + fluoropyrimidine), PD-L1+ | -PFS, OS- in PD-L1+ | -PFS, OS -TTP, ORR | 592 | Pending |
| Pembrolizumab | NCT02335411 (KEYNOTE-059) | II | Active, not recruiting | -PEMBRO or PEMBRO + chemo (CISPLATIN + 5-FU/CAPECITABINE) | -Recurrent/metastatic GC/GEJ adenocarcinoma | -% AE, discontinuation of treatment due to AE -ORR | - | 316 | Pending |
| Pembrolizumab | NCT03277352 | I/II | Recruiting | -INCAGN01876 + PEMBRO + EPACADOSTAT | -Advanced/ metastatic malignancies | -% AE -ORR, CRR (RECIST) | -ORR, DCR, DOR, PFS, OS (rECIST, mRECIST) | 166 | Pending |
| Pembrolizumab | NCT02443324 | I | Active, not recruiting | -PEMBRO + RAMUCIRUMAB | -GC/GEJ (NSCLC, transitional urothelial cancer, biliary tract cancer) | -DTL | -% BOR of CR/PR, ORR -% SD -DOR, time to response -PFS, OS -Pharmacokinetics | 155 | Pending |
| Avelumab | NCT02625623 (JAVELIN GASTRIC 300) | III | Active, not recruiting | -AVE + BSC vs -chemo+BSC/BSC | -Unresectable, recurrent, locally advanced/ metastatic GC/GEJ adenocarcinoma (3rd line) | -OS | -PFS, BOR -QOL | 37 | Pending |
| Avelumab | NCT03399071 (ICONIC) | II | Recruiting | -AVE + chemo (FLOT) | -Perioperative setting, operable EC/GC | -Pathol CR | -% grade 3-4 AE -Radiologic response (RECIST) -median PFS, OS | 40 | Pending |
| Avelumab | NCT02625610 (JAVELIN GASTRIC 100) | III | Active, not recruiting | -AVE maintenance vs Ist line continuation of chemo (OXALIPLATIN + FLUOROPYRIMIDINE) | -Unresectable, locally advanced/ metastatic GC/GEJ adenocarcinoma | -OS, PFS | -BOR (RECIST) -QOL -% AE | 499 | Pending |
| Avelumab | NCT01943461 (JAVELIN SOLID TUMOR JPN) | I | Active, not recruiting | -AVE | -Locally advanced/ metastatic solid tumors (Japan) → expansion part GC patients (Asia) | -DLT | -Concentration assessment, elimination half-life -% PD-L1 -BOR+ irBOR, PFS +irPFS -OS % Ab-anti AVE -% AE | 57 | Pending |
| Avelumab | NCT03475953 (REGOMUNE) | I/II | Not yet recruiting | -AVE + REGORAFENIB | -Advanced/metastatic digestive solid tumors (including GC) | -Recommended doses -Assessment of Regorafenib antitumor activity -Pharmacokinetics | -Maximum tolerated dose -DLT -% AE -BOR, ORR, PFS, OS -Blood/tumor growth biomarkers | 212 | Pending |
| Avelumab | NCT02554812 (JAVELINE Medley) | Ib/II | Recruiting | -AVE + other immunotherapies → AVE + PD 0360324 (M-CSF mAb) (gastric cancer) | -Locally advanced/ metastatic solid tumors (including GC) | -% DLT -ORR | -Serum concentration of drugs -Ab-anti drugs -TTR, DOR, PFS, OS -Tumor biomarkers (PD-L1, CD8+T cells) | 560 | Pending |
| Durvalumab | NCT02734004 (MEDIOLA) | I/II | Active, not recruiting | -DURVA + OLAPARIB (PARP inhibitor) | -Advanced solid tumors (including GC) | -DCR (at CT/MRI) -% AE -Safety- vital signs, blood samples | -% PD-L1 -DCR (mRECIST) -Time to treatment discontinuation) -OS -% change in tumor size (CT/MRI) -Serum concentration of Ab-anti drug -Pharmacokinetics -ORR, DOR, PFS (mRECIST) | 148 | Pending |
| Durvalumab | NCT02572687 | I | Active, not recruiting | DURVA + RAMUCIRUMAB | -Locally advanced unresectable/ metastatic gastrointestinal (including GC/GEJ adenocarcinoma) and thoracic malignancies | -% DLT | -ORR, DCR -DOR, TTR -PFS -OS -Pharmacokinetics -% Ab-anti drug | 114 | Pending |
| Durvalumab | NCT02678182 (PLATFORM) | II | Recruiting | -DURVA vs. CAPECITABINE vs. TRASTUZUMAB vs. RUCAPARIB vs. surveillance | -Maintenance treatment, locally advanced/ metastatic HER2+/-EG, adenocarcinoma (after Ist line chemo) | -PFS (RECIST) | -PFR -OS, ORR (RECIST) -% AE -PFS, PFR, OS, ORR according to PD-L1 immunohistochemical status | 770 | Pending |
| Durvalumab | NCT02264678 | I/II | Recruiting | -AZD6738 ± Chemo/OLAPARIB/DURVA | -Advanced malignancies (including GC) | -Safety, tolerability (AE, SAE) | -Pharmacodynamics, biomarker changes -Serum concentration of drug, half-life, etc. -BOR, ORR, % change in tumor size | 250 | Pending |
NIVO: Nivolumab; IPI: Ipilimumab; TREME: Tremelimumab; DURVA: Durvalumab; PEMBRO: Pembrolizumab; AVE: Avelumab, TRAS: Trastuzumab; Chemo: Chemotherapy; AE: Adverse events; SAE: Serious adverse events; DLT: Dose limiting toxicities; DOR: Duration of response; OS: Overall survival; QOL: Quality of life; PFS: Progression free disease; ir-PFS: Immune-related progression free disease; PFR: Progression-free rate; ORR: Objective response rate; RR: Response rate; pathCR: Pathologic complete response, RFS: Relapse-free survival; DR: Disease response; DDC: Duration disease control; BOR: Best objective response; DCR: Disease control rate; PD: Progressive disease; CR: Complete response; PR: Partial response; SD: Stable disease; TTR: Time to response; NET: Neuroendocrine tumors; SqCC: Squamous cell carcinoma; GIST: Gastrointestinal stromal tumors; EBV: Epstein Barr virus; N/A: Not applicable.